Synaptotagmin 7 is targeted to the axonal plasma membrane through γ-secretase processing to promote synaptic vesicle docking in mouse hippocampal neurons

• Published in: eLife Vol. 10
• Main Authors: Vevea, Jason D, Kusick, Grant F, Courtney, Kevin C, Chen, Erin, Watanabe, Shigeki, Chapman, Edwin R
• Format: Journal Article
• Language: English
• Published: England eLife Sciences Publications Ltd 20.09.2021; eLife Sciences Publications, Ltd
• Subjects: Alzheimer's disease; Amyloid Precursor Protein Secretases - metabolism; Animals; Axon guidance; Axons - enzymology; Axons - ultrastructure; Cell Membrane - enzymology; Cell Membrane - ultrastructure; Cells, Cultured; Electron microscopy; Exocytosis; Experiments; gamma secretase; Hippocampus; Hippocampus - enzymology; Hippocampus - ultrastructure; iGluSnFR; Lipoylation; Localization; Membrane proteins; Membranes; Mice; Mice, Knockout; Molecular Docking Simulation; Neuronal Plasticity; Neuroscience; Paired-pulse facilitation; Palmitoylation; Protein Processing, Post-Translational; Protein Transport; Proteolysis; Rats; Rats, Sprague-Dawley; Secretase; short-term synaptic plasticity; Synaptic plasticity; Synaptic Transmission; Synaptic vesicles; Synaptic Vesicles - enzymology; Synaptic Vesicles - ultrastructure; Synaptotagmin; Synaptotagmin 7; Synaptotagmins - genetics; Synaptotagmins - metabolism; Time Factors; zap-and-freeze; zap-and-freeze; mouse; hippocampus; rat; gamma secretase; neuroscience; iGluSnFR; short-term synaptic plasticity; Synaptotagmin 7
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.67261

Synaptotagmin 7 (SYT7) has emerged as a key regulator of presynaptic function, but its localization and precise role in the synaptic vesicle cycle remain the subject of debate. Here, we used iGluSnFR to optically interrogate glutamate release, at the single-bouton level, in SYT7KO-dissociated mouse hippocampal neurons. We analyzed asynchronous release, paired-pulse facilitation, and synaptic vesicle replenishment and found that SYT7 contributes to each of these processes to different degrees. ‘Zap-and-freeze’ electron microscopy revealed that a loss of SYT7 diminishes docking of synaptic vesicles after a stimulus and inhibits the recovery of depleted synaptic vesicles after a stimulus train. SYT7 supports these functions from the axonal plasma membrane, where its localization and stability require both γ-secretase-mediated cleavage and palmitoylation. In summary, SYT7 is a peripheral membrane protein that controls multiple modes of synaptic vesicle (SV) exocytosis and plasticity, in part, through enhancing activity-dependent docking of SVs.